Invasive Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATelet Inhibition and patient Outcomes trial Outcomes in patients with a Planned Invasive Strategy The PLATO trial was funded by AstraZeneca Dr. Cannon discloses research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems

Efficacy of clopidogrel is hampered by PLATO background In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel Efficacy of clopidogrel is hampered by slow and variable transformation to the active metabolite (e.g. 2C19) modest and variable platelet inhibition  risk stent thrombosis and MI in poor responders Irreversible effect – and increased risk of bleeding if urgent CABG is required PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y12 receptor Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of circulating platelets within ~48 hours

PLATO study design NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Clopidogrel (n=6,676) If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre-PCI) Ticagrelor (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

Baseline and index event characteristics Ticagrelor (n=6,732) Clopidogrel (n=6,676) Median age, years 61.0 Age ≥75 years, % 12.5 13.9 Women, % 25.2 25.3 Diabetes mellitus 22.8 23.7 History, % Myocardial infarction Percutaneous coronary intervention Coronary-artery bypass graft 17.1 14.1 5.3 17.0 13.3 5.7 ECG and Troponin at entry, % Persistent ST-segment elevation ST-segment depression T-wave inversion 48.4 52.8 28.7 49.3 54.0 29.4 Troponin-I positive (central lab, first) % 82.3 84.0 Median time from chest pain to rand., h 8.8 9.0

Procedures and timing* Ticagrelor (n=6,732) Clopidogrel (n=6,676) Invasive procedures at index hospitalization, % (n) Coronary angiography Median (IQR), hours PCI during index hospitalization % (n) UA/NSTEMI – PCI % (n) STEMI - Primary PCI % (n) Coronary by-pass surgery pre-discharge % (n) 96.8 (6514) 0.62 (0.10, 3.70) 76.7 (5166) 0.77 (0.30, 2.75) 63.8 (1882) 2.63 (0.78, 21.10) 83.2 (3138) 0.47 (0.23, 0.95) 5.5 (372) 117 (47, 216) 96.9 (6471) 0.62 (0.12, 3.65) 77.1 (5148) 0.78 (0.32, 2.65) 64.8 (1854) 2.60 (0.87, 21.30) 82.7 (3149) 0.48 (0.23, 0.95) 6.1 (410) 121 (48, 218) * Time between randomization and first procedure

Co-medication Medication Ticagrelor (n=6,732) Clopidogrel (n=6,676) Anti-thrombotic treatment in hospital, % Aspirin Unfractionated heparin Low molecular weight heparin Fondaparinux Bivalirudin GP IIb/IIIa inhibitor 97.7 35.1 41.1 1.6 1.2 19.7 97.9 36.0 40.9 1.8 1.3 20.3 Other medication in hospital or at discharge, % Beta-blockade ACE /ARB Cholesterol lowering (statin) Proton pump inhibitor 85.5 87.0 95.4 54.4 86.1 86.8 95.5 53.7

Clopidogrel / Ticagrelor treatment Prior to hospitalization 7.3 6.7 Open-label Clopidogrel pre-Randomization, % None or missing information 75 mg 300 mg 600 mg 55.3 8.3 19.3 17.1 54.7 8.1 19.8 16.6 Study drug Clopidogrel (or placebo for Tic) in first 24 h None Total Clopidogrel (OL+IP) pre-Randomization to 24 h Premature discontinuation of study drug, % 1.5 44.2 46.4 8.0 69.1 30.9 23.1 1.4 46.5 69.9 30.1 21.8

Primary endpoint: CV death, MI or stroke 15 Clopidogrel 10.65 10 9.02 K-M estimated rate (% per year) Ticagrelor 5 HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor 6,732 6,236 6,134 5,972 4,889 3,735 3,048 Clopidogrel 6,676 6,129 6,034 5,881 4,815 3,680 2,965 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Hierarchical testing of major efficacy endpoints Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value† Primary objective, % CV death + MI + stroke 9.0 10.7 0.84 (0.75–0.94) 0.0025 Secondary objectives, % Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events MI CV death Stroke 9.4 13.2 5.3 3.4 1.2 11.2 15.3 6.6 4.3 1.1 0.85 (0.77–0.93) 0.80 (0.69–0.92) 0.82 (0.68–0.98) 1.08 (0.78–1.50) 0.001 0.0005 0.002 0.025 0.646 Total (all-cause) death 3.9 5.1 0.81 (0.68–0.95) 0.010 *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. †By univariate Cox model

Myocardial infarction Cardiovascular death 8 8 Clopidogrel 6.6 6 6 5.3 Cumulative incidence (%) Clopidogrel Ticagrelor Cumulative incidence (%) 4.3 4 4 3.4 Ticagrelor 2 2 HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025 60 120 180 240 300 360 60 120 180 240 300 360 Days after randomization Days after randomization No. at risk Ticagrelor 6,732 6,268 6,173 6,010 4,924 3,766 3,078 6,732 6,439 6,375 6,241 5,141 3,591 3,233 Clopidogrel 6,676 6,157 6,062 5,917 4,849 3,706 2,987 6,676 6,376 6,332 6,209 5,114 3,917 3,164

Days after randomization All-cause mortality 6 Clopidogrel 5.08 4 3.94 Ticagrelor K-M estimated rate (% per year) 2 HR 0.81 (95% CI = 0.68–0.95), p=0.01 60 120 180 240 300 360 No. at risk Days after randomization Ticagrelor 6,732 6,439 6,375 6,241 5,141 3,951 3,233 Clopidogrel 6,676 6,376 6,331 6,209 5,114 3,917 3,164

Stent thrombosis Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value* Stent thrombosis, % Definite Probable or definite Possible, probable, or definite 1.0 1.7 2.2 1.6 2.3 3.1 0.62 (0.45–0.85) 0.72 (0.56–0.93) 0.72 (0.58–0.90) 0.003 0.01 ¶ Evaluated in patients with any stent during the study Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization * By univariate Cox model

Primary efficacy endpoint by clopidogrel loading dose KM % at Month 12 Hazard Ratio (95% CI) Total Patients p value (Interaction) Characteristic Ti. Cl. HR (95% CI) Clopidogrel loading dose (Pre-rand. + Study drug) 0.917 300 mg 9314 9.5 11.2 0.85 (0.74, 0.96) 600 mg 4091 8.0 9.5 0.83 (0.67, 1.03) 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better

Primary safety event: Major bleeding* 15 Clopidogrel 11.6 Ticagrelor 11.5 10 K-M estimated rate (% per year) 5 HR 0.99 (95% CI = 0.89–1.10), p=0.88 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor 6,651 5,235 4,947 4,755 3,726 2,741 2,503 Clopidogrel 6,585 5,215 4,984 4,786 3,753 2,754 2,496 * PLATO definitions

Life-threatening or fatal bleeding* No. at risk Clopidogrel Ticagrelor 6,585 6,651 5,400 5,387 5,180 5,113 5,009 Days from first IP dose 3,934 3,890 2,898 2,866 2,635 2,634 60 120 180 240 300 360 6 2 8 4,945 HR 1.04 (95% CI = 0.90–1.20), p=0.61 4 5.9 6.0 K-M estimated rate (% per year) * PLATO definitions

K-M estimated rate (% per year) PLATO life-threatening/ fatal bleeding Total major bleeding 13 NS Ticagrelor Clopidogrel 12 11.5 11.6 11 NS 10 NS 8.9 9 8.8 8.0 8.0 8 7 NS K-M estimated rate (% per year) 6.0 6 5.9 5 4 3 2 NS 1 0.2 0.3 PLATO major bleeding TIMI major bleeding Red cell transfusion PLATO life-threatening/ fatal bleeding Fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; NS = not significant

Non-CABG and CABG-related major bleeding 13 NS Ticagrelor Clopidogrel 12 11.5 11.6 11 4.7 10 NS 9 4.1 Non-CABG 8.0 8.0 8 7 K-M estimated rate (% per year) 2.3 2.8 6 5 NS 4 CABG 3.2 2.9 3 1.7 2 1.9 1 PLATO major bleeding TIMI major bleeding GUSTO severe bleeding* *Preliminary – from eCRF

Bradycardia-related events and other findings All patients Ticagrelor (n=6,732) Clopidogrel (n=6,676) p value* Bradycardia-related event, % Any bradycardia event Symptomatic event Sick sinus syndrome or sinus pause AV Block II-III Temporary pacemaker used Permanent pacemaker implanted Considered serious adverse event 5.5 2.1 0.4 0.5 0.8 1.0 5.1 2.4 0.6 1.1 0.26 0.24 0.89 0.15 1.00 0.73 Dyspnea, % Any dyspnea event Requiring discontinuation of study- treatment 15.4 0.9 10.4 0.3 <0.0001 < 0.0001 *p values calculated using Fisher’s Exact test

Therapeutic considerations Based on 1,000 patients admitted to hospital for ACS and planned for invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths 13 fewer myocardial infarctions 6 fewer cases with stent thrombosis No increase in major bleeding or need for transfusion 6 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea Treating 59 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke Treating 88 will save one life (in one year)

for the continuous prevention of ischemic events, Conclusions Ticagrelor, the reversible, more intense P2Y12 antagonist, is a more effective alternative to clopidogrel for one year in ACS patients managed with an invasive strategy, for the continuous prevention of ischemic events, stent thrombosis and death without an increase in major bleeding